Repeat infusions of naive immune B-cells were safe and delayed disease onset, reduced disease severity, and extended survival in animal models of amyotrophic lateral sclerosis (ALS), a study found.

The approach was also deemed safe in the treatments first in-human case study, in which it eased disease severity and reduced biomarkers of inflammation in a person with advanced ALS.

We were able to show safety and efficacy, as well as how the B cell therapy worked in mice, and we demonstrated that our approach was safe and feasible in a human, senior author Mark C. Poznansky, MD, PhD, an attending physician at Massachusetts General Hospital (MGH) and a professor of medicine at Harvard Medical School, said in a hospital press release.

Details of the potential new B-cell therapy were published in The FASEB Journal in the study, Allogeneic B cell immunomodulatory therapy in amyotrophic lateral sclerosis.

This is a first study of its kind to apply B cells to the treatment of ALS and sets us up for a trial of this new treatment approach to a currently incurable disease, said Poznansky, who is also the director of the Vaccine and Immunotherapy Center at MGH.

Elevated inflammation is known to play a role in the onset and progression of ALS, a condition marked by the loss of motor neurons, the nerve cells that control certain body movements.

Mitigating neuroinflammation via immune targeting may provide an effective therapeutic strategy for attenuating neuronal loss in ALS, the researchers wrote.

B-cells are best known as the immune cells that produce antibodies to protect the body from infections and other harmful substances. But recent research has demonstrated that these cells can also respond to tissue injury, help rebalance immune function, and coordinate tissue repair.

Previous work by lead author Ruxandra F. Srbulescu, PhD, assistant professor of neurology at Harvard Medical School, showed that naive B-cells reduced inflammation and promoted recovery in mice with skin or brain injuries.

These benefits were driven by a process the team dubbed pligodraxis, in which B-cells can adopt immunoregulatory and neuroprotective properties.

What we observed early on in preclinical studies has been a remarkable effect of B cells in the context of brain lesions both brain structure and function were protected by treatment with these cells, which made us consider applying them as a therapeutic in the context of neurodegenerative disease, Srbulescu said.

A team led by Srbulescu and Poznansky tested this type of B-cell therapy in an ALS mouse model and, for the first time, an individual with ALS.

The ALS mouse model carried mutations in the SOD1 gene, a known ALS-related gene. The mice received 10 weekly doses of mature naive B-cells isolated from the spleens of donor mice, administered directly into the bloodstream.

Results showed that the B-cell treatment was safe and significantly delayed disease onset compared with a control treatment. Treated animals also tended to have better neurological function, indicating less severe disease, and a longer survival time, though the differences between groups failed to reach statistical significance.

Tissue analyses showed significantly less abnormal or dying motor neurons, as well as reduced markers of neuroinflammation.

We were able to show that B cells, which can be readily obtained from the blood, could treat ALS in a well-established mouse model of the disease, and we obtained permission from the US Food and Drug Administration and our hospital to try this treatment approach in an individual with ALS, Poznansky said.

The participant was a man in his 50s who received a diagnosis of ALS following the onset of bulbar symptoms, which affect the muscles of the face, jaw, and throat, impairing speech and swallowing. He was being treated with the standard ALS treatment riluzole (sold as Rilutek, among other brand names).

B-cells were collected from the participants adult child, who was an immunological match, and infused into the patients bloodstream twice, 60 days apart. This was deemed was safe and did not trigger an abnormal inflammatory response.

After the first infusion, the patient had a modest improvement in scores on the revised ALS Functional Rating Scale (ALSFRS-R), an assessment of disease severity that measures the ability to perform everyday activities.

After the second infusion, the participants ALSFRS-R score again improved but gradually declined, as expected in ALS, thereafter. The participant withdrew from the study on day 136.

Blood tests showed marked treatment-related reductions in markers for body-wide inflammation and in pro-inflammatory immune cells.

Still, levels of neurofilament light chain, a marker of nerve cell damage, continued to rise, suggesting that the intervention at a relatively late/end stage of disease progression would be insufficient to halt neurodegenerative processes, the researchers wrote.

A Phase 1 trial will be needed to further evaluate the safety and efficacy of this novel approach to treating ALS, the researchers concluded. Such a trial is now in the planning stage, Poznansky said.

Continued here:
New B-cell therapy eases disease severity, delays onset: Study - ALS News Today

Blocking the TGF- signalling pathway produced effective antitumour activity against hepatocellular carcinoma.

Scientists at the University of California San Diego have discovered that genetically modified NK-cell therapy improves the targeting and treatment of hepatocellular carcinoma (HCC), the most treatment-resistant form of solid tumour.

Unlike chimeric antigen receptor (CAR)-expressing T-cell therapy, the NK treatment does not require personalisation, meaning it could be mass produced and shelf-ready for patients to begin therapy without delay. Dr Dan Kaufman, lead study author and director of the Sanford Advanced Therapy Center, explained: To some extent all tumour cells perhaps hepatocellular carcinoma more so inhibit immune cells that try to kill themThis is one key reason why some immunotherapies like CAR T cells have been less successful for solid tumours than for blood cancers the immunosuppressive tumour microenvironment.

The researchers produced stem cell-derived NK cells in which the receptor for transforming growth factor beta (TGF-) was disabled. The liver and HCC tumours contain a high amount of TGF-, which inhibits immune cell activity and enables cancer to grow. It was discovered that typical NK cells without the disabled receptor, like CAR T cells, were not effective in destroying the cancer. When they assessed the modified NK cells, Dr Kaufman stated: we got very good antitumour activity and significantly prolonged survival.

These studies demonstrate that it is crucial to block transforming growth factor beta at least for NK cells, but I also think its true for CAR T cells, Dr Kaufman added. If you unleash NK cells by blocking this inhibitory pathway, they should kill cancer quite nicely.

In the future, Dr Kaufman believes their findings will aid clinical trials of numerous research groups and companies, whether they study CAR T-cell or NK-cell therapies and tackle hepatocellular carcinoma or other difficult types of solid tumours. He concluded: Anyone developing such therapies for solid tumours should be working to inhibit transforming growth factor beta activity to improve cancer-killing and attain effective anti-tumour activity.

This study was published in Cell Stem Cell.

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Treating HCC with genetically modified NK-cell therapy - Drug Target Review

When Mindy's previous treatment stopped working for multiple myeloma, she opted for CAR-T cell therapy.

Following an infection that was resistant to treatment and a few extra blood tests, the doctor advised me to see a hematologist (that was OK!) or an oncologist (not so good to hear). In January 2007, the diagnosis of multiple myeloma was followed by several new normals for my family and me.

Let the journey begin. What is myeloma? How do my husband and I tell and support my daughters (one finishing high school and the other in college)? How do I support my husband? Will I survive this? Who will be there to support me? What treatments will I need? Can I trust my doctor to provide the best treatment for me? Who are all these strange people in the clinic? What about my friends? My co-workers? Would they treat me the same? Who will understand what I am going through? After letting the diagnosis set in, while I was ready to fight this battle, I did not realize what a challenge this would be. I was faced with so many factors out of my control.

Fast forward 16 years. It took lots of energy, questioning, researching and talking. Some of my questions and fears were addressed, but new ones were constantly popping up. I remained in the working world for more than 13 years, sometimes walking from my office building to Massey Cancer Center in Richmond, Virginia for treatment. One autologous (my stem cells) transplant. One allogeneic (donor) transplant. Yes, I am now my brother! And thank goodness for my brothers loving generosity. Seven years of partial remission after transplants. What happened during these 16 years? Too many times, I heard that my numbers were stable followed by the news that my numbers were slowly climbing. More treatment regimens. It was an emotional roller coaster as I moved forward.

I cherished amazing inspiration, support and laughs from my dear family, my health care team, friends and other myeloma colleagues. I had completed several half-marathons to support The Leukemia & Lymphoma Society; organized and co-led a local International Myeloma Foundation support group; and volunteered at Massey Cancer Center. These activities kept me connected with my community, others who were impacted and it raised my resiliency.

The best celebrations enriching my life that I never expected was witnessing my daughters become beautiful, caring, compassionate, strong professional women; becoming a mother-in-law; and then becoming a grandmother! Life goes on in beautiful ways. For this, I am grateful.

In 2023 after two years of a specific treatment regimen that kept my numbers stable that tricky myeloma figured out a way to stump us again. Now what? CAR-T cell therapy? Bispecific antibodies? How grateful that I have options, but still anxious moving forward. I chose CAR-T cell therapy for the one and done option. The beginning of my CAR-T cell therapy journey was a little scary and only a bit bumpy. But, it was well worth the effort to power through! Twelve months after CAR-T cell therapy, I am still in complete remission and living my best life!

My favorite sayings during my journey have been This too shall pass and It is what it is. If I could use two words to describe my journey, they are hope and resilience. How are hope and resilience part of your story?

This post was written and submitted byMindy C. Fast. The article reflects the views ofFastand not of CURE. This is also not supposed to be intended as medical advice.

For more news on cancer updates, research and education, dont forget tosubscribe to CUREs newsletters here.

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My Decision to Receive CAR-T Cell Therapy for Multiple Myeloma - Curetoday.com

Hot on the heels of receiving the FDAs coveted Regenerative Medicine Advanced Therapy (RMAT) designation for its Lomecel-B product, Longeveron this week revealed its lead cell therapy has also been granted Fast Track designation for the treatment of mild Alzheimers. The Miami-based biotech has now received five different FDA designations for Lomecel-B, and this latest one should help streamline its development and expedite its review as a potential Alzheimers therapy.

The Fast Track designation comes on the back of compelling Phase 2 trial results, which demonstrated that Lomecel-B slowed or prevented the progression of Alzheimers in some groups of patients with the mild form of the disease. Longeverons aim is now to move the therapy into the next phase of trials in Alzheimers as soon as possible, potentially as early as next year. But the company is not putting all its eggs in one basket

Longevity.Technology: Derived from the bone marrow of young, healthy adult donors, Lomecel-B, a so-called living cell product, has demonstrated pro-vascular, pro-regenerative and anti-inflammatory effects. With multiple mechanisms of action, the drug is being explored for its potential in several indications, spanning neurodegeneration, frailty and heart conditions. Could we be looking at a longevity drug in the making? To learn more, we caught up with Longeveron CEO, Wael Hashad.

Longeveron was founded with a mission to target age-related diseases, which are often characterized by chronic inflammation, combined with a decline in immune system and blood vessel function. The companys approach involves building therapeutics, like Lomecel-B, from special living cells called medicinal signaling cells (MSCs) derived from donated bone marrow tissue.

One of the key mechanisms through which MSCs exert their therapeutic benefits is by releasing exosomes, growth factors and other proteins, such as anti-inflammatory cytokines, which have the potential to significantly reduce inflammation, while stimulating the promotion of regenerative and repair responses. This is why, rather than targeting amyloid plaques or neurofibrillary tangles, Longeveron is going after the inflammation of the central nervous system that is increasingly recognized as a driver of neurodegeneration in Alzheimers.

With preliminary clinical data showing that Lomecel-B simultaneously targets multiple aging-related processes, Hashad explains that an important part of the recent Phase 2 Alzheimers trial was demonstrating these effects in humans.

We wanted to see if there was any data supporting the hypothesis of the mechanism of action, which is the anti-inflammatory and pro-vascular effect of the drug, he says. So, in addition to other clinical scales that you typically use in Alzheimers trials, we also added MRI measurement of brain volumes, which is a very objective exploratory endpoint.

This means that, in addition to study results showing that Lomecel-B was safe, well-tolerated, and demonstrated statistically significant improvements in specified cognitive function measurements in certain groups, Longeveron also generated some compelling MRI data.

We got a big, positive surprise from the effect that we saw on the MRI, which indicated that there was less shrinkage in the brain compared to placebo, says Hashad. And that was significant, not just on the total volume of the brain, but also on the hippocampal volume, which is the memory formation center of the brain.

This data, Hashad believes, was instrumental in the company receiving the recent designations from the FDA, which should help accelerate the process to move Lomecel-B forward as a potential treatment for mild Alzheimers.

Recent FDA guidance for Alzheimers disease indicates that clinical trials showing an effect on a surrogate endpoint that is determined to be reasonably likely to predict clinical benefit can be the basis for accelerated approval. The MRI data from the Phase 2 trial, which can be considered a surrogate endpoint, may significantly expedite the development and approval process for Lomecel-B.

We can now have a much more active dialogue with the FDA, and potentially discuss the possibility of an accelerated approach to bring the product to the market using surrogate endpoints, for example, he says. The next step is to meet with the FDA before the end of the year to talk about the blueprint for the next phase of development.

With chronic inflammation also heavily implicated in many other age-related conditions, Longeveron believes that the anti-inflammatory, pro-vascular mechanism of Lomecel-B can also play a role beyond the brain.

We have an indication that Lomecel-B may work by reducing levels of inflammation, and also improving the health of the vascular system and therefore the blood supply and the blood flow to the brain and other areas of the body, says Hashad.

In addition to its program in Alzheimers, Lomecel-B is also being explored as a treatment for age-related frailty, as well as a congenital heart condition called hypoplastic left heart syndrome (HLHS).

Age-related frailty, or sarcopenia, is thought to affect around 15% of individuals aged 65 and older, and significantly heightens the risk of adverse clinical outcomes from disease and injury. Despite its prevalence, no medical treatments for the condition have been approved by the FDA or any other regulatory body.

Longeveron has commenced multiple clinical trials of Lomecel-B in frailty but has faced some challenges in terms of determining the endpoints needed to demonstrate efficacy to the FDA.

We have seen good data in our studies, but there is no product approved for aging related frailty, and were still trying to get an agreement with the FDA on what that indication is, says Hashad. So far, what we have used in our trials is the six-minute walk test, which evaluates the distance a patient can walk within six-minutes. We have seen a statistically significant improvement in our Phase 2 study with this metric at nine months. We will continue to work with the FDA which also wants to see a more objective assessment as well, so were trying to get alignment on that before we proceed forward on that program.

Longeverons more recent work in cardiology is of keen interest to the companys founder, the renowned cardiologist Dr Joshua Hare. While the program is currently focused on a rare, inherited condition, Hashad admits that the company is exploring the potential to target other heart-related indications.

There are certain things that were working on that I cannot disclose at this time, he says. But cardiology remains one of Joshs biggest passions, and we believe that Lomecel-B may have multiple potential applications within the heart disease area as well as other products that were also working on.

So, if Lomecel-B goes on to prove successful in multiple age-related diseases, would that make it a potential longevity drug? Hashad doesnt bite, although he does believe the therapy could have more applications in other diseases.

As a startup, we must focus on the work that we currently have at hand, but hopefully, as we continue to advance our work and grow, then we can embark on other areas of disease that can also benefit patients in the future, he says. There is no doubt that life expectancy is increasing around the world the question is how we ensure that people are not just living longer but living longer with a better quality of life, whether by improving their heart health, muscle health, or brain health. We believe that Lomecel-B, and the other products that were working on in our labs, can potentially help to improve that quality of life.

Continued here:
Cell therapy shows potential in multiple age-related diseases - Longevity.Technology

Taiga Nishihori, MD, senior member in the Blood & Marrow Transplant and Cellular Immunotherapy Department at Moffitt Cancer Center, discusses a study in which investigators evaluated patients with relapsed and/or refractory (R/R) multiple myeloma who were hospitalized and treated with commercial ciltacabtagene autoleucel (cilta-cel; Carvykti) at Moffitt Cancer Center between May 2022 and May 2023.

Patients in the initial group to be evaluated were given lymphodepleting chemotherapy as outpatient, followed by chimeric antigen receptor (CAR) T-cell infusion as inpatient. Patients were also monitored, then discharged to an outpatient immune cell therapy service. The first 30 days post-infusion was the focus of the study.

Transcription:

0:09 | We wanted to look at our experience on treating patients with multiple myeloma who received cilta-cel, which is a CAR T-cell [therapy]. We started looking at this in 2022. Initially, we started doing an outpatient model, which was the beginning of it, and then we changed it to inpatient. The chemotherapy was given, lymphodepletion in particular, and chemotherapy was given as an outpatient; they readmitted patients. But then, we quickly realized that patients who are in the hospital were basically spending a lot of time waiting for toxicity to occur. We changed our approach entirely outpatient. And then we looked at over 20 patients who received those. We also demonstrated that the amount of time they spend in a hospital has been cut down from 11 days to a median of 4 days.

1:11 | We wanted to look at the hospital duration. We also wanted to look at the outcomes of this approach. We have established our system to take care of patients, mostly on the outpatient side. The patients are seen daily in what is called 3 central outpatient areas, and we have managed to conduct this safely as an outpatient.

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Study Focuses on Outpatient CAR T-Cell Therapy in Multiple Myeloma - Targeted Oncology

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Excerpt from:
Designing drug delivery systems for cell therapy - Nature.com

Once a month, Talaya Reid wakes up early to board a flight from Philadelphia to Boston, in hopes of impacting research into lupus and the potential benefits of chimeric antigen receptor (CAR) T cell therapy to treat the chronic autoimmune disease.

Reid travels to UMass Chan Medical School in Worcester to participate in an individualized clinical research study exploring the use of CAR T cell treatment in lupus nephritis for severe or nonresponsive lupus. The Lupus Center at UMass Chan is one of five national sites participating in the trial sponsored by Kyverna Therapeutics. Reid is one of a dozen patients in the United States to have undergone CAR T cell treatment for lupus.

Ive participated in treatments before that have calmed my lupus symptoms down, but the symptoms were still there, or the treatments did nothing at all. When I heard it was possible to live without lupus symptoms or flare ups anymore, I was very interested in participating in this trial, Reid said.

Roberto Caricchio, MD, theMyles J. McDonough Chair in Rheumatology, professor of medicine, chief of the Division of Rheumatology in the Department of Medicine and director of the Lupus Center at UMass Chan, is principal investigator of the CAR T cell therapy trial in lupus at UMass Chan.

This treatment is not for everyone. It is for those patients who unfortunately have gone through several treatments that we have available and somehow the lupus does not seem to be matched by them. Its a significant, but restricted group of patients. And within that group of patients, it takes a special individual who is looking for something different and commits to something new, Dr. Caricchio said.

Lupus is a chronic autoimmune disease that involves multiple organ systems and often requires lifelong treatment with immunosuppressive or immunomodulatory drugs, which are not effective for all patients. Lupus nephritis is a complication of lupus that causes inflammation of the kidneys, impacting the bodys ability to remove waste from the blood or regulate body fluids.

"Ive participated in treatments before that have calmed my lupus symptoms down, but the symptoms were still there, or the treatments did nothing at all. When I heard it was possible to live without lupus symptoms or flare ups anymore, I was very interested in participating in this trial."

CAR T cell therapy has been recognized as a significant advancement in treating cancers such as leukemia, lymphoma and more recently, multiple myeloma. CAR T cells are created by removing some of a patients white blood cells, including immune system T cells, and genetically altering them in a lab to produce CARs. These changes help the patient's T cells identify and kill antigens on the outside of the harmful cells once they are put back into the body.

Reids first treatment in March required a two-week hospital stay, during which she underwent lymphodepletion chemotherapy and an infusion of her CAR T cells and was monitored by medical personnel in the Blood and Marrow Transplant program at UMass Memorial Medical Center. She stayed in the Worcester area for three weeks after her discharge from the hospital before transitioning to monthly visits.

Each monthly visit to the Lupus Center at UMass Chan requires an assessment by a trained provider and extensive bloodwork at UMass Memorial Medical Center-Memorial Campus. During her day-long visit, Reid has more than 15 vials of blood taken. The blood samples are separated into two categories: for future Lupus research and for understanding what the CAR T cell therapy treatment is doing for her.

Once her bloodwork is completed, Reid travels back to Boston to catch a plane home to Philadelphia.

If her lupus symptoms havent flared up again, she will only need to come to Worcester for one visit in 2025. She will continue to be observed by the Lupus Center at UMass Chan for at least two years.

As of now, I can say that this is the best I've ever felt. I feel really good, said Reid, 28, a pharmaceutical scientist from Fairless Hills, Pennsylvania, who was diagnosed with lupus at 22. She said her flares previously ranged from minimalfatigue or discomfortto major, with joint pain and/or migraines that impacted her ability to attend college classes or work.

According to Caricchio, the Lupus Center has enrolled a second patient in the CAR T cell therapy trial who is expected to begin treatment in July.

This treatment not only helps the patients currently participating in these trials, but also future patients, Caricchio said. It has been a very strong learning experience. The plus is that this type of treatment isnt only groundbreaking but will also teach us a lot about lupus itself as a disease and we will be able to capitalize on that and find better ways to help patients.

Caricchio cautioned that all results are preliminary, saying, It is important to remember that this is an experimental treatment and therefore only upon completion of the clinical trial will we know if this approach is truly transformative for lupus patients.

The Lupus Center is led by Caricchio and Elena Gkrouzman, MD, assistant professor of medicine, and includes a team of dedicated experts, including rheumatologists, dermatologists and nephrologists, as well as clinical research coordinators.

The CAR T cell therapy clinical trial at the Lupus Center at UMass Chan is conducted in collaboration with the Cancer Research Office at the UMass Cancer Center; the Blood Cancer Center physicians and teams, including Jan Cerny, MD, PhD, associate professor of medicine; Muthalagu Ramanathan, MD, professor of medicine; and Poorva Bindal, MD, assistant professor of medicine; and the Divisions of Hematology/Oncology and Renal Medicine/Nephrology.

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Lupus Center at UMass Chan investigating CAR T cell therapy for severe or nonresponsive lupus nephritis - UMass Medical School